Exploring the therapeutic potential of cannabidiol for sleep deprivation-induced hyperalgesia.

Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potency in addressing this particular issue remains to be determined. Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity. CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.

Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder prevalent in school-age children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit gamma 8 (CACNG8)) is an auxiliary AMPA receptor (AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD, whereby adolescent TARP γ-8 knockout (KO) mice exhibited ADHD-like behaviors, including hyperactivity, impulsivity, anxiety, impaired cognition, and memory deficits. Human single-nucleotide polymorphism (SNP) analysis also revealed strong associations between intronic alleles in CACNG8 genes and ADHD susceptibility. In addition, synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice. Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice. Methylphenidate (MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans. This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8 deficiency, which has great potential for the development of new therapies.

Ropivacaine Inhibits Lung Cancer Cell Malignancy Through Downregulation of Cellular Signaling Including HIF-1α In Vitro.

Background: Ropivacaine is widely used to induce regional anesthesia during lung cancer surgery. Previous studies reported that amide-linked local anesthetics, e.g., ropivacaine, affected the biological behavior of lung adenocarcinoma cells, but the conclusion is controversial and warrants further study. This study set out to investigate the biological effects of ropivacaine on cultured lung cancer cells and underlying mechanisms. Methods: Lung cancer cell lines (A549 and H1299) were cultured and then treated with or without ropivacaine (0.5, 1, and 2 mM) for 48 or 72 h. Their proliferation, migration, and invasion together with cell death and molecules including hypoxia inducible factor (HIF)-1α, VEGF, matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 expression associated with these changes were determined. Results: Ropivacaine significantly inhibited proliferation and migration, invasion, and cell death in a concentration-dependent manner in both cell lines. Ropivacaine also promoted cell death and induced a concentration- and time-dependent cell arrest towards the G0/G1 phase. Expression of VEGF, MMP-1, MMP-2, MMP-9, and HIF-1α in both cell lines was also inhibited by ropivacaine in a concentration-related manner. Conclusion: Our data indicated that ropivacaine inhibited lung cancer cell malignancy, which may be associated with downregulation of cell-survival-associated cellular molecules. The translational value of the current work is subjected to further study.

Dexmedetomidine alleviates cisplatin­induced acute kidney injury by attenuating endoplasmic reticulum stress­induced apoptosis via the α2AR/PI3K/AKT pathway.

Cisplatin (CP) is an effective antineoplastic agent; however, CP­induced acute kidney injury (AKI) seriously affects the prognosis of patients with cancer. Endoplasmic reticulum (ER) stress (ERS)­induced apoptosis serves a pivotal role in the pathogenesis of CP­induced AKI. Dexmedetomidine (Dex), a potent α2 adrenergic agonist, has been reported to exert protective effects against AKI. However, the protective effects of Dex against CP­induced AKI and the potential molecular mechanisms remain unknown. In the present study, male Sprague­Dawley rats were divided into four groups (n=10/group), as follows: Control group; CP group, rats received an intraperitoneal (i.p.) injection of 5 mg/kg CP; Dex + CP group, rats received an i.p. injection of 25 µg/kg Dex immediately after CP treatment; and Dex + CP + atipamezole (Atip) group, rats received an i.p. injection of 250 µg/kg Atip, an α2 adrenoreceptor (α2AR) antagonist, and then received the same treatment as the Dex + CP group. Rats were anesthetized and sacrificed 96 h after CP injection. Subsequently, serum blood urea nitrogen (BUN) and serum creatinine (Scr) were analyzed, and kidney samples were collected for analyses. Pathological changes were examined using hematoxylin and eosin staining, and protein expression levels were assessed using western blotting and immunohistochemical staining. In addition, apoptosis was examined using a terminal deoxynucleotidyl transferase dUTP nick­end labeling assay. The present results suggested that Dex protected against CP­induced AKI by attenuating histological changes in the kidney, serum BUN and Scr production. Furthermore, the expression levels of 78­kDa glucose­regulated protein, C/EBP homologous protein and caspase­12, and the apoptotic rate in the kidney were decreased following Dex treatment. In addition, the expression levels of phosphorylated (p)­PI3K and p­AKT in the Dex + CP group were significantly increased. Conversely, the renoprotective effects of Dex were attenuated following the addition of Atip. In conclusion, Dex may alleviate CP­induced AKI by attenuating ERS­induced apoptosis, at least in part, via the α2AR/PI3K/AKT signaling pathway.

[Effects of dexmedetomidine on perioperative cardiac adverse events in elderly patients with coronary heart disease].

OBJECTIVE: To investigate the effects of dexmedetomidine on perioperative cardiac adverse events in elderly patients with coronary heart disease.
 Methods: Sixty elderly patients, who were diagnosed as coronary heart disease and underwent gastric cancer operation, were randomly divided into 2 groups (n=30): the dexmedetomidine group (Dex group) and the control group. In the Dex group, dexmedetomidine was administered intravenously at 0.5 µg/(kg·h) after a bolus infusion at 0.5 µg/kg for 10 min before anesthesia induction. In the control group, equal volume of normal saline was infused instead of dexmedetomidine. The 2 groups received the same anesthesia treatment. The venous bloods were collected at the preoperative 0 h and postoperative 24 h. The concentrations of cardiac troponin (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP) and hypersensitive C-reactive protein (hs-CRP) were determined. The ECG was monitored at the above time and the postoperative incidence of cardiac adverse events was recorded.
 Results: The levels of cTnI, NT-proBNP and hs-CRP in serum were elevated in the 2 groups after the operation. Compared with the control group, the levels of cTnI, NT-proBNP and hs-CRP were significantly decreased in the Dex group (P<0.05). Compared with the control group, the incidence of bradycardia were significantly increased, while the myocardial ischemia and tachycardia were significantly decreased in the Dex group during the operation (P<0.05); the incidence of silent myocardial ischemia and arrhythmia was significantly reduced at 3 days after operation in the Dex group (P<0.05).
 Conclusion: Dexmedetomidine could decrease the incidence of cardiac adverse events in elderly patients with coronary heart disease.